1. Field of the Invention
This invention relates to novel water-soluble azole compounds useful for the treatment of serious systemic fungal infections and suitable for both oral and, particularly, parenteral administration. More particularly, the invention relates to novel water-soluble prodrugs having the general formula ##STR1##
wherein R and R.sup.1 are each independently hydrogen or (C.sub.1 -C.sub.6)alkyl, Z is nitrogen or CH, Q is the residue of an azole compound of the formula ##STR2##
possessing antifungal activity, X.sup..crclbar. is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.
2. Description of the Prior Art
Azole antifungal compounds are well-known in the prior art. U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H,1,2 ,4-triazol-1-yl)-butan-2-ol has potent antifungal activity. ##STR3##
The utility of this class of compounds is limited by their low water-solubility. For example, the solubility of the above triazole compound in water at pH 6.8 is 0.0006 mg/mL. This greatly impedes developing suitable parenteral dosage forms.
One method of addressing the solubility problem is disclosed in European Published Application 829,478 where the water-solubility of an azole antifungal agent was increased by attaching a linked amino-acid to the azole portion of the molecule. ##STR4##
Alternatively, WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula ##STR5##
Published European Patent Application 829,478 discloses water-soluble azole compounds of the general formula ##STR6##
wherein
Q is the remainder of an azole compound of the formula ##STR7## PA1 Z is nitrogen or methine; PA1 R.sup.1 and R.sup.2 are each independently hydrogen or --OY in which Y is an easily hydrolyzable ester; PA1 R.sup.3 and R.sup.4 are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower-alkylcarbonyl)thiomethyl, carboxy or methoxycarbonyl; and X.sup..crclbar. is a pharmaceutically acceptable anion.
possessing antifungal activity;
Published PCT Application WO 98/43970 discloses quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compounds where one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo and the substituent can be eliminated in vivo to be converted into an azole antifungal compound. Specifically disclosed are prodrugs wherein the nitrogen atom of the azole ring is quaternized by a group of the formula ##STR8##
wherein R.sup.1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R.sup.2 is a hydrogen atom or a lower alkyl group; X is a nitrogen atom or a methine group; and n is 0 or 1.